DESCRIPTION: Aging is a fundamental process characterized by an increase in mortality rates with time and a progressive change in phenotypes. The molecular causes of aging are not understood. One approach to uncovering causes is to identify genes that determine the life span of an organism. The model system S. cerevisiae affords the opportunity to identify mutants that increase life span (i.e., the number of cell divisions undergone by mother cells) and thus highlight genes that are important in the aging process. In the previous granting period, Dr. Guarente used one approach to identify such mutants, thus demonstrating the feasibility of the yeast system. These mutants have provided a link between the loss of chromosome silencing by the SIR complex and aging. It was found that old cells were defective in silencing, and that the life span of this organism could be influenced by mutations in silencing proteins. In this application, Dr. Guarente plans to dissect further this important link between aging and silencing in S. cerevisiae. New genetic screens have been developed to identify more novel genes that are important in yeast aging. These experiments will provide a comprehensive study of yeast aging. Findings in yeast may be related to mammalian systems, first by identifying mammalian homologs of key yeast genes and relating them to life span in a mouse model, and second, by determining whether those cellular processes that are critical in yeast aging are affected by aging in a mammal.